Natural regulatory T cells (Tregs) are actively selected in the thymus and exert potent suppressive activity in the periphery for the induction and maintenance of tolerance. These cells are characterised by a distinct phenotype including high expression of cell surface proteins CD25 and GITR, high intracellular expression of CTLA-4, but absence of IL-7R. They are anergic and hyporesponsive in the absence of exogenous growth factors, and do not produce IL-2. Expression of the transcription repressor Foxp3 is the hallmark of such natural Tregs. The suppressive activity of natural Tregs was shown to be linked to a defect in phosphorylation of AKT, a serine-threonine kinase dependent of phosphatidylinositide-3 kinase (PI3K; Crellin et al. (2007) Blood 109: 2014-2022).
The use of such natural Tregs in controlling immune disorders by adoptive cell transfer is severely limited by the very low frequency of cells of defined specificity, the difficulty to expand them in vitro and by the absence of efficient methods by which they can be expanded in vivo. Besides, the functional activity of natural regulatory T cells is non-specific, as they produce suppressive cytokines such as IL-10 and TGF-beta. Hence, there is a need for suppressor T cells with increased specificity that are in addition more amenable to expansion.